Abstract 4555: Inhibition of CDK1/2 but not CDK4/6 cooperates with tamoxifen to induce apoptosis

Abstract

Abstract As essential drivers of cell cycle progression and transcription, cyclin-dependent kinases (CDKs) often become dysregulated during tumorigenesis, thus motivating extensive efforts towards development of CDK inhibitors as a new class of promising anticancer agents with clear CDK specificity including those targeting mainly CDK4 and CDK6 (e.g. PD0332991, LY2835219) vs. those primarily targeting CDK1 and CDK2 (e.g. BMS265246, Dinaciclib). Given there different cyclin dependencies and mitotic phase mechanisms, including the relative cell cycle independence of some CDKs, specific CDK inhibitors are expected to exhibit different anticancer activities, side effects, and interactions with other anticancer agents, and require different clinical biomarkers. With regard to breast cancers in which at least 75% overexpress estrogen receptor (ER, alpha isoform), it is particularly important to establish the type of CDK inhibitor most effective in combination with anti-estrogenic agents like tamoxifen or aromatase inhibitors. To preclinically determine the potential added efficacy of specific CDK inhibition in combination with anti-estrogen therapy, the ER-positive human breast cancer cell line MCF7 was used to compare the relative efficacy of CDK1/2 inhibition vs. CDK4/6 inhibition in combination with 4-hydroxytamoxifen (Tam) in promoting breast cancer cell death (apoptosis). These studies were also designed based on our recent evidence that CDK1/2 inhibition, but not CDK4/6 inhibition, suppressed transcriptional upregulation of ER inducible genes by impairing ER hinge domain phosphorylation at Ser294, suggesting that CDK1/2 inhibition would preferentially cooperate with Tam to impair ER-positive breast cancer viability by their convergent suppression of ligand-dependent ER transcription. We confirmed this hypothesis by demonstrating that CDK1/2 inhibitors, but not CDK4/6 inhibitors, suppressed ligand induced ER phosphorylation at Ser294, without altering Ser118 phosphorylation which remained constant despite either CDK1/2 or CDK4/6 inhibition. Consistent with its ability to suppress ER phosphorylation at Ser294, CDK1/2 inhibition, in combination with Tam, enhanced MCF7 apoptosis, while CDK4/6 inhibition had no such cooperative effect. These ER-positive breast cancer cell line and molecular studies should guide further preclinical and clinical efforts in evaluating the optimal choice of CDK inhibitor for use in combination with endocrine agents. These findings also suggest that clinical emphasis should be placed on the evaluation of CDK1/2 inhibitors in combination with anti-estrogens like tamoxifen, where loss of ER phosphorylation at Ser294 can also be used as an early biomarker of response to monitor this therapeutic combination. Citation Format: Gary K. Scott, Daniel Rothschild, Ravneet Kaur, Christopher Benz. Inhibition of CDK1/2 but not CDK4/6 cooperates with tamoxifen to induce apoptosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4555. doi:10.1158/1538-7445.AM2014-4555